EP2265643B1 - Schema posologique pour traiter le psoriasis et l'arhtrite rhumatoide - Google Patents

Schema posologique pour traiter le psoriasis et l'arhtrite rhumatoide Download PDF

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EP2265643B1
EP2265643B1 EP09727585.3A EP09727585A EP2265643B1 EP 2265643 B1 EP2265643 B1 EP 2265643B1 EP 09727585 A EP09727585 A EP 09727585A EP 2265643 B1 EP2265643 B1 EP 2265643B1
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antibody
domain
dose
chain
cells
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EP2265643A1 (fr
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Frank Osterroth
Silke Aigner
Matthias Germer
Christoph Uherek
Elmar Kraus
Andrea Wartenberg-Demand
Daniele Wolf
Sibylle Kaiser
Juergen Lindner
Christoph Bruecher
Benjamin Daelken
Gregor Schulz
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Biotest AG
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Biotest AG
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Priority claimed from GB0817811A external-priority patent/GB0817811D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2812—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the present invention is concerned with treatment of autoimmune diseases.
  • the invention involves a highly effective agent which is a humanised monoclonal antibody that may be administered to patients in lower dosages than previously known. It is particularly effective for patients having diseases or characteristics requiring lower doses for effective treatment.
  • the description envisages a pharmaceutical composition comprising the antibody in efficacious concentration, as well as uses and methods of treatment employing the compositions and medicaments comprising the antibody.
  • Autoimmunity is the failure of an organism to recognise its own constituent parts (down to sub-molecular levels) as "self", which results in an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease.
  • Autoimmune diseases include multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, colitis ulcerosa, Crohn's disease, myasthenia gravis (MG), autoimmune polyglandular syndrome type II (APS-II), Hashimoto's thyroiditis (HT), type-1 diabetes (T1D), systemic lupus erythematosus (SLE) and autoimmune lymphoproliferative syndrome (ALS).
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • psoriasis psoriatic arthritis
  • colitis ulcerosa Crohn's disease
  • MG myasthenia gravis
  • Activation of 'autoreactive' T cells by presentation of autoantigens processed by antigen presenting cells (APC) leads to their clonal expansion and migration to the specific tissues, where they induce inflammation and tissue destruction.
  • APC antigen presenting cells
  • T cells are tolerant with regard to autologous tissue and only react on presentation of heterologous structures.
  • Central tolerance and peripheral tolerance comprise the two mechanisms by which the immune system hinders the autoreactive T cells from inducing their deleterious functions.
  • Central tolerance is mediated through negative selection. This process entails the elimination, through clonal deletion of autoreactive T cells, during ontogenic development in the thymus.
  • Peripheral tolerance is the backup available if central tolerance fails and autoreactive cells escape the thymus. This mechanism of tolerance occurs continuously throughout life, keeping autoreactive cells in check through immune ignorance (anergy), peripheral deletion and active suppression.
  • T regulatory cells (Tregs, formerly also designated “suppressor cells”) as part of active suppression maintain peripheral tolerance and regulate autoimmunity ( Suri-Payer et al., J Immunol. 157: 1799-1805 (1996 ); Asano et al., J Exp. Med. 184:387-396 (1996 ); Bonomo et al., J. Immunol. 154: 6602-6611 (1995 ); Willerford et al., Immunity 3: 521-530 (1995 ); Takahashi et al., Int. Immunol.
  • Tregs Several subsets of regulatory T cells have been characterized.
  • the family of Tregs consists of two key subsets: naturally arising e.g. CD4 + CD25 + Tregs and peripherally induced, Tr1 and Th3 Tregs.
  • NKTregs and CD8 + Tregs have been described in humans and rodents ( Fehérvari et al., J. Clin. Investigation 114: 1209-1217 (2004 )).
  • Thymus-derived Treg cells are the main regulatory cells involved, utilizing an array of TCRs targeted towards autoantigen recognition in order to maintain immune homeostasis in the periphery, and regulate autoimmunity and pathogenic immune responses.
  • Tregs The role of Tregs is exemplified best by experiments involving reconstitution of immunodeficient nude mice with CD4 + cells that were depleted of CD25 + cells.
  • CD4 + CD25 - reconstituted nude mice develop various organ-specific autoimmune diseases, such as gastritis, oophoritis, orchitis, and thyroiditis ( Suri-Payeret al.; J. Immunol. 160: 1212-1218 (1998 )).
  • CD4 + CD25 + subset prevents the onset of these diseases ( Sakaguchi et al., J Immunol. 155: 1151-1164 (1995 )).
  • the protective value of CD4 + CD25 + cells against organ-specific autoimmunity has also been shown in several other models of autoimmunity (e.g. autoimmune gastritis, prostatitis, oophoritis, glomerulonephritis, epidimytis and thyroiditis) caused by neonatal thymectomy performed 3 days after birth (d3Tx) or inflammatory bowel disease caused by reconstitution of SCID mice with CD45RBhigh, CD4 + CD25 - T cells.
  • Administration of anti-CD25 antibody in vivo in mice also induces organ-localised autoimmune disease.
  • CD4 + CD25 + Tregs inhibit polyclonal and antigen-specific T cell activation.
  • the suppression is mediated by a cell contact-dependent mechanism that requires activation of CD4 + CD25 + Tregs via the TCR but Tregs do not show a proliferative response upon TCR activation or stimulation with mitogenic antibodies (anergic) ( Shevach, Nature Rev. Immunol 2 : 389 (2002 ).
  • mitogenic antibodies anergic
  • Type 1 T regulatory (Tr1) cells and Th3 cells.
  • Tr1 Type 1 T regulatory
  • Tr1 cells were induced by repetitive stimulation of TCR in the presence of IL-10 and were shown to mainly down-regulate immune responses via the production of high levels of IL-10 and moderate amounts of TGF- ⁇ ( Chen et al., J. Immunol. 171: 733-744 (2003 )).
  • Th3 cells (identified in a model of EAE after oral delivery of antigen) produce high amounts of TGF- ⁇ and variable amounts of IL-4 and IL-10, and IL-4 was shown to be a key factor for the differentiation of Th3 cells, in contrast to Tr1 cells ( Chen et al., Science 265:1237-1240 (1994 )).
  • immunosuppressive drugs Suppression of T cell function by using immunosuppressive drugs is a principal therapeutic strategy that has been used successfully to treat autoimmune diseases.
  • these drugs induce a general immunosuppression due to their poor selectivity, resulting in inhibition of not only the harmful functions of the immune system, but also useful ones.
  • several risks like infection, cancer and drug toxicity may occur.
  • T cell function agents interfering with T cell function are therapeutic mainstays for various autoimmune diseases.
  • TGN 1412 Treatment with a total dose of 5-10 mg of TGN 1412 (0.1 mg anti-CD28 per kilogram of body weight) lead to a systemic inflammatory response with multiorgan failure within 90 minutes after receiving a single intravenous dose of the TGN 1412 ( Suntharalingam et al, N Engl. J Med. 2006 Sep 7;355(10):1018-28 ).
  • CD4 + T cells play a major part in initiating and maintaining autoimmunity. Accordingly, it has been proposed to use mAbs against CD4 + T cells surface molecules, and in particular anti-CD4 mAbs, as immunosuppressive agents. Although numerous clinical studies confirmed the potential interest of this approach, they also raised several issues to be addressed in order to make anti-CD4 mAbs more suitable for use in routine clinical practice.
  • CD4 mAbs Several different mechanisms of action for CD4 mAbs have been proposed including: (1) antagonism of CD4-MHC II interactions resulting in inhibition of T cell activation, (2) CD4 receptor modulation as determined by a decrease in cell surface expression of CD4, (3) partial signaling through the CD4 receptor in the absence of T cell receptor cross-linking which can suppress subsequent T cell activation and trigger CD4 T cell apoptotic death, (4) Fc-mediated complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC) leading to CD4 T cell depletion, and (5) stimulation of regulatory T cells.
  • CDC complement-dependent cytotoxicity
  • ADCC antibody-dependent cellular cytotoxicity
  • the B-F5 antibody (murine IgG1 anti-human CD4) was tested in different autoimmune diseases.
  • Rhadot et al. discloses the immunological follow-up of 17 patients with rheumatoid arthritis treated in vivo with an anti-T CD4+ monoclonal antibody (B-F5), (Clin. Exp. Rheumatol., 1992, 10(4):365-374 ).
  • Wendling et al. discloses the treatment of rheumatoid arthritis with anti CD4 monoclonal antibody; open study of 25 patients with the B-F5 clone (Clin. Rheumatol., 1992; 11(4):542-547 ).
  • MS multiple sclerosis
  • humanized antibodies obtained by grafting the complementarity-determining regions (CDRs) of a mouse monoclonal antibody, which determine the antigen-binding specificity, onto the framework regions (FRs) of a human immunoglobulin molecule.
  • the aim of humanization is to obtain a recombinant antibody having the same antigen-binding properties as the mouse monoclonal antibody from which the CDR sequences were derived, and far less immunogenic in humans.
  • substituting CDRs from the mouse antibody for the human CDRs in human frameworks is sufficient to transfer the antigen-binding properties (including not only the specificity, but also the affinity for antigen).
  • some FR residues are important for antigen binding, because they directly contact the antigen in the antibody-antigen complex, or because they influence the conformation of CDRs and thus their antigen binding performance.
  • hB-F5 humanized B-F5
  • compositions for parenteral administration of from 0.1-10 mg, preferably from 1-5 mg.
  • Dosage regimes envisaged are an intravenous 1 mg per day dose and a 5 mg every second day dose for rheumatoid arthritis patients over a period of 10 days.
  • Wijdenes et al. in an abstract and poster presented at the EULAR conference, June 2005. They described the treatment of 11 patients suffering from rheumatoid arthritis with 5 intravenous infusions of 5 mg BT061 every other day with concomitant treatment with 150 mg Diclophenac ( Wijdenes et al., Abstract and poster, EULAR conference, June 2005 ).
  • the antibody described in this study is not disclosed to be suitable for use in lower doses, and it is still desirable to find treatments at lower doses so as to treat a greater number of patients.
  • the present invention provides a pharmaceutical composition for use in treating psoriasis or rheumatoid arthritis comprising a pharmaceutically acceptable carrier and a humanized anti-CD4 antibody capable of activating CD4+CD25+ regulatory T cells, wherein the composition is to be administered to a subject in a dose of the humanized anti-CD4 antibody of 0.2 mg to 5 mg and is to be administered intravenously, wherein the composition is to be administered weekly, every two weeks, every four weeks, every calendar month, or every six weeks, wherein the humanized anti-CD4 antibody comprises an H chain V domain, an L chain V domain, and an IgG1 constant domain, and wherein the H chain V domain is defined by SEQ ID No: 1 and the L chain V domain is defined by SEQ ID No: 2.
  • the invention further provides a pharmaceutical composition for use in treating psoriasis or rheumatoid arthritis in a subject comprising a pharmaceutically acceptable carrier and a humanized anti-CD4 antibody capable of activating CD4+CD25+ regulatory T cells, wherein the subject is to receive a plurality of doses of the composition, wherein the composition is to be administered to the subject in a total dose of the humanized anti-CD4 antibody over a period of 10 days of between 0.2 and 7.5 mg, wherein the composition is to be administered intravenously, wherein the humanized anti-CD4 antibody comprises an H chain V domain, an L chain V domain, and an IgG1 constant domain, and wherein the H chain V domain is defined by SEQ ID No: 1 and the L chain V domain is defined by SEQ ID No: 2.
  • the invention provides a pharmaceutical composition for use in treating psoriasis or rheumatoid arthritis comprising a pharmaceutically acceptable carrier and a humanized anti-CD4 antibody capable of activating CD4+CD25+ regulatory T cells, wherein the composition is to be administered to a subject in a dose of the humanized anti-CD4 antibody of 2 to 20 ⁇ g/kg and is to be administered intravenously, wherein the composition is to be administered weekly, every two weeks, every four weeks, every calendar month, or every six weeks, wherein the humanized anti-CD4 antibody comprises an H chain V domain, an L chain V domain, and an IgG1 constant domain, and wherein the H chain V domain is defined by SEQ ID No: 1 and the L chain V domain is defined by SEQ ID No: 2.
  • the present invention provides a use of a humanized anti-CD4 antibody capable of activating CD4+CD25+ regulatory T cells for the manufacture of a pharmaceutical composition for treating psoriasis or rheumatoid arthritis wherein the composition is to be administered to a subject in a dose of the humanized anti-CD4 antibody of 0.2 mg to 5 mg and is to be administered intravenously, wherein the composition is to be administered weekly, every two weeks, every four weeks, every calendar month, or every six weeks, wherein the humanized anti-CD4 antibody comprises an H chain V domain, an L chain V domain, and an IgG1 constant domain, and wherein the H chain V domain is defined by SEQ ID No: 1 and the L chain V domain is defined by SEQ ID No: 2.
  • the present invention provides a use of a humanized anti-CD4 antibody capable of activating CD4+CD25+ regulatory T cells for the manufacture of a pharmaceutical composition for treating psoriasis or rheumatoid arthritis in a subject, wherein the subject is to receive a plurality of doses of the composition, wherein the composition is to be administered to the subject in a total dose of the humanized anti-CD4 antibody over a period of 10 days of between 0.2 mg and 7.5 mg, wherein the composition is to be administered intravenously, wherein the humanized anti-CD4 antibody comprises an H chain V domain, an L chain V domain, and an IgG1 constant domain, and wherein the H chain V domain is defined by SEQ ID No: 1 and the L chain V domain is defined by SEQ ID No: 2.
  • the present invention provides a use of a humanized anti-CD4 antibody capable of activating CD4+CD25+ regulatory T cells for the manufacture of a pharmaceutical composition for treating psoriasis or rheumatoid arthritis, wherein the composition is to be administered to a subject in a dose of the humanized anti-CD4 antibody of 2 to 20 ⁇ g/kg, wherein the composition is to be administered intravenously, wherein the composition is to be administered weekly, every two weeks, every four weeks, every calendar month, or every six weeks, wherein the humanized anti-CD4 antibody comprises an H chain V domain, an L chain V domain, and an IgG1 constant domain, and wherein the H chain V domain is defined by SEQ ID No: 1 and the L chain V domain is defined by SEQ ID No: 2.
  • low dosages of the antibody BT061 provided effective and specific activation of naturally occurring regulatory T cells (CD4 + CD25 + Tregs) providing an in vivo clinical effect at far lower doses than those previously used, such as those disclosed in WO 2004/083247 .
  • the humanized antibody BT061 did not substantially modulate levels nor induce release of pro-inflammatory cytokines, as compared to other T cell interacting antibodies, for example anti-CD3 antibodies. Further the antibody does not cause a substantial long term depletion of CD4+ lymphocytes.
  • the concentration of the antibody is not especially limited, provided that it is present in a concentration that is low compared to known concentrations.
  • the concentration of the antibody is from 0.1 ⁇ g/ml to 30 mg/ml or, 0.1 to 1000 ⁇ g/ml, and more preferably from 1-500 ⁇ g/ml and 2-250 ⁇ g/ml.
  • the concentration of the antibody is (approximately) any one of 15 ⁇ g/ml, 25 ⁇ g/ml, 125 ⁇ g/ml, 250 ⁇ g/ml, 500 ⁇ g/ml, 1 mg/ml, 12.5 mg/ml or 25 mg/ml.
  • the dosage volume applied to a subject using the composition is not especially limited, provided that it delivers a low overall dosage compared to dosages already known, and is therefore suitable for all patients because of a lower level of side effects and especially in the treatment of individuals who do not tolerate doses as disclosed in WO 2004/083247 .
  • the concentration of the antibody within the dosage volumes can be varied in order to provide the required dosages which are described in this application.
  • the dosage volume will vary depending on the method of administration.
  • the composition is to be administered by intravenous infusion.
  • the dosage volume may be from 0.1 or 0.5 ml up to 500 ml, preferably between 15 and 25 ml, and typically about 20 ml.
  • the composition may be provided in concentrated form and diluted to the strength required for the individuals concerned.
  • the composition is provided in relatively small volumes of about 1, 2, 3, 4 or 5 ml.
  • the composition is provided at the required strength and dosage volume described above (i.e. ready for administration).
  • agents capable of treating autoimmune disease could be administered in the low dosages that are envisaged by the present invention. Whilst known doses of agents capable of treating autoimmune disease are effective in some individuals or disease types, the realisation that it may be effective already in much lower doses has opened up the way for more effective treatment of some autoimmune diseases and classes of patients.
  • the agents that are suitable for use in the present description are those which are capable of activating CD4+CD25+ regulatory T cells.
  • the agent may be a polypeptide, a protein or an antibody. Where the agent is an antibody it may be a monoclonal antibody. Preferably the antibody is a monoclonal anti-CD4 antibody.
  • the antibody may also preferably be an IgG1 antibody and may be an unmodified IgG1 antibody.
  • the agent does not cause a substantial increase in the level of pro-inflammatory cytokines in the subject's blood plasma after administration as compared to the levels seen after administration of anti-CD3 antibodies.
  • the levels of IFN- ⁇ , TNF- ⁇ , IL-6 and/or IL-2 after administration of the agent are not substantially raised compared to plasma levels measured in healthy subjects (see Table A1).
  • the ULN for a specific cytokine given in Table A1 is taken as X then within 96 hours after administration of the agent there may be less than a 20 fold increase in X.
  • cytokine levels prior to administration of the agent are already higher than those observed in healthy subjects (ULN given in Table A1) e.g. due to a modified activation status of immune cells compared to the activation status of the cells in healthy subjects.
  • the concentration for a specific cytokine directly prior to administration of the agent is taken as X and within 96 hours after administration of the agent there may be less than a 20 fold increase in X. Preferably there may be less than a 10 fold increase in X. More preferably these levels are during the period of 10 minutes after the start of administration to 96 hours after the completion of administration.
  • Table A1 Cytokine levels measured in plasma of healthy volunteers. The ULN (upper limit of normal) is calculated based on mean values measured in 39 individual subjects + 2 x standard deviation.
  • the agent does not cause a substantial long-lasting decrease in the cell count of CD4+ lymphocytes in the subject's blood plasma.
  • the cell count of CD4+ lymphocytes in the subject's blood plasma may be above 250 cells/ ⁇ l (or at least 250 cells/ ⁇ l).
  • cytokine and CD4+ lymphocyte effects described above are seen in at least 80% of patients treated.
  • the agent is an unmodified IgG1 antibody, i.e. an antibody which does not include an Fc mutation, and has not been subject to deglycosylation, glycomodification or glycoengineering to reduce Fc receptor interactions, or a fragment or a derivative thereof.
  • the antibodies which are most suitable for use in the present description are humanized anti-CD4 antibodies, or fragments or derivatives thereof, which are capable of activating CD4+CD25+ regulatory T cells. Examples of antibodies which are capable of activating CD4+CD25+ regulatory T cells are discussed in Becker et al., (European Journal of Immunology (2007), Vol. 37: pages 1217-1223 ).
  • the antibody used in the description comprises one or more variable domains which are capable binding to CD4.
  • the antibody may comprise a human constant region (Fc).
  • This constant region can be selected among constant domains from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgG1, IgG2, IgG3 and IgG4.
  • Preferred constant regions are selected among constant domains of IgG, in particular IgG1.
  • the present description also includes any fragment of the antibody comprising the V regions thereof. This comprises in particular Fab, Fab', F(ab)' 2 , Fv and scFv fragments.
  • the antibody is a humanized anti-CD4 antibody or fragment or derivative thereof derived from the mouse monoclonal anti-CD4 antibody B-F5.
  • An example of such an antibody is the BT061 antibody.
  • the humanized antibody BT061 (hB-F5) is derived from mouse B-F5 mAb, and has V domains defined by the following polypeptide sequences:
  • Derivatives of this antibody are also suitable for use in the present descriptoin.
  • Derivatives include those with V domains defined by polypeptide sequences having at least 80%, preferably at least 90%, most preferably at least 95% sequence identity with SEQ ID NO: 1 or SEQ ID NO: 2.
  • Particularly preferred antibodies are those which comprise the complementarity-determining regions (CDRs) of the mouse B-F5 mAb, and retain the ability of hB-F5 to activate CD4+ CD25+ regulatory T cells.
  • CDRs complementarity-determining regions
  • the location of the CDRs within the V H and V K domains is shown in Figures 20 and 21 .
  • Such antibodies can optionally have variations in the sequence of the CDRs that do not substantially affect the specificity and/or affinity of binding.
  • the hB-F5 antibody used further comprises a human constant region (Fc).
  • this constant region can be selected among constant domains from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including IgG1, IgG2, IgG3 and IgG4.
  • Preferred constant regions are selected among constant domains of IgG, in particular IgG1.
  • the present description also includes any fragment of the hB-F5 antibody or derivative thereof comprising the V regions thereof. This comprises in particular Fab, Fab', F(ab)' 2 , Fv and scFv fragments.
  • a polynucleotide encoding the V domain of the H chain or of the L chain of a BT061 antibody may be fused with a polynucleotide coding for the constant region of a human H or L chain, for the purpose of expressing the complete H and L chains obtained in this way; a sequence coding a signal peptide allowing the secretion of the protein can also be added.
  • the description also makes use of expression cassettes wherein a polynucleotide as described above is linked to appropriate control sequences allowing the regulation of its transcription and translation in a chosen host cell, and recombinant vectors comprising a polynucleotide or an expression cassette of the description.
  • recombinant DNA constructs can be obtained and introduced in host cells by the well-known techniques of recombinant DNA and genetic engineering.
  • the description also makes use of a host cell, transformed by a polynucleotide of the description.
  • a host cell transformed by a polynucleotide of the description.
  • Useful host-cells within the framework of the present description can be prokaryotic or eukaryotic cells.
  • suitable eukaryotic cells one will mention, by way of example, plant cells, cells of yeasts such as Saccharomyces , cells of insects such as Drosophila , or Spodoptera, and mammal cells such as HeLa, CHO, 3T3, C127, BHK, COS, etc.
  • the BT061 (hB-F5) antibody used in the invention can be obtained by culturing a host cell containing an expression vector comprising a nucleic acid sequence encoding said antibody, under conditions suitable for the expression thereof, and recovering said antibody from the host cell culture.
  • DNA sequences encoding mouse B-F5 V H and V K regions are respectively shown in Figure 3 and Figure 4 and under sequence identifiers SEQ ID NO:5 and SEQ ID NO:6.
  • the human V H and V K on which the mouse CDRs are grafted were selected by searching databases for human V H most like the original mouse B-F5 V H and V K .
  • V H region of a human antibody (M26; Accession Number A36006) had the highest homology with B-F5 V H .
  • VK region of another human antibody FK-001; NAKATANI et al., Biotechnology, 7 (1989), 805-810 ) had the highest homology with B-F5 V K .
  • V K Two types of V K differing between them in that the 4 th residue was Leucine or Methionine were constructed and designated as L4L and L4M.
  • VH Two types of VH differing between them in that the 37 th amino acid residue was Leucine or Valine, were constructed and designated as H37L and H37V.
  • the alignment of the polypeptide sequences of B-F5, M26, H37L, and H37V is shown in Figure 21 .
  • the FR residues previously reported to be important for the packing of CDRs Chothia et al., Nature 342(1989), 877 ; Foote et al., J. Mol. Biol., 224(1992), 487 ) are boxed.
  • V H and V K By combining these V H and V K , 4 versions of V regions were designed.
  • expression plasmids for the H chain V H humanized region fused to the constant region of a human y-1 chain ( TAKAHASHI et al., Cell, 29 (1982), 671-679 )
  • L chain VK humanized region fused to the constant region of FK-001 K chain
  • Figure 5 and 6 respectively show the fragments of the plasmids encoding the VH and V K regions of humanized BF-5.
  • Culture supernatants of transfectomas producing the four versions of hB-F5 were collected, and concentrated.
  • the different antibodies were purified from culture supernatants by affinity chromatography using protein A Sepharose and assessed for their CD4 binding activity by measuring, by means of competitive ELISA, their inhibitory activities against the binding of biotinylated mB-F5 to soluble CD4 coated on microtiter plates. Incubation, time is 2 hours for 37°C and overnight for 4°C.
  • H37L/L4L and H37L/L4M were chosen for evaluation.
  • mice B-F5 and humanized B-F5s H37L/L4M IgG1 and H37L/L4L IgG 1 were evaluated.
  • Humanized B-F5s of IgG2 type H37L/L4M IgG2 and H37L/L4L IgG2 were also tested.
  • PBMCs peripheral blood mononuclear cells
  • Murine and hB-F5s could moderately inhibit ConA-induced proliferation, but the activities varied from antibody to antibody and/or from donor to donor. Also, murine and hB-F5s were able to inhibit Ag-specific PBMC proliferation induced by PPD.
  • IgG1 type of hB-F5 inhibited PPD-induced proliferation more effectively (as high as 70% inhibition) than mB-F5.
  • IgG1 type seemed to be more effective than IgG2 type of which inhibitory activity was almost the same as mB-F5.
  • H37L/L4M was more effective than H37L/L4L.
  • IgG2 type of H37L/L4M and H37L/L4L had almost the same inhibitory activities.
  • H37L/L4M IgG1 was chosen for further evaluation, and it is this antibody which is named BT061 and is employed to demonstrate the present invention in the Examples provided in this application.
  • the pharmaceutical composition and medicaments used in the present description are preferably capable of treating an autoimmune disease in patients benefiting from lower doses.
  • Such patients include all patients because of a lower level of side effects but especially individuals who do not tolerate doses as disclosed in WO 2004/08324 .
  • the present description also provides use of a humanized anti-CD4 antibody or fragment or derivative thereof in the manufacture of a medicament effective against an autoimmune disease, wherein the humanised antibody capable of activating CD4+CD25+ regulatory T cells, and wherein the medicament comprises the antibody in a concentration of from 10 ⁇ g/ml to 150 mg/ml, preferably from 0.5 mg/ml to 75 mg/ml.
  • the description further provides use of a humanized anti-CD4 antibody or fragment or derivative thereof in the manufacture of a medicament effective against an autoimmune disease, wherein the humanised antibody is capable of activating CD4+CD25+ regulatory T cells, and wherein the medicament is administered to a subject in a single dose or a plurality of doses in an amount of the antibody of from 0.2 to 30 mg per dose.
  • the present description also provides a pharmaceutical composition for treating an autoimmune disease comprising a pharmaceutically acceptable carrier and an agent capable of activating CD4+CD25+ regulatory T cells, wherein the composition is to be administered to a subject in a dose of the agent from 0.2 mg to 30 mg, 0.2 to 20 mg per dose, 0.3 mg to 7.5 mg, 0.3 to 5 mg per dose or preferably 0.3 to 1 mg per dose. Most preferably the range of milligrams per dose extends between 0.3 mg to 0.9 mg, or 0.3 to 0.99 mg.
  • the subject is to receive a plurality of doses.
  • dosage over a period of 10 days is between 0.2 to less than 25 mg, more preferably between 0.2 and 20 mg and most preferably between 0.2 to less than 10 mg.
  • the dosage over a period of 5 days should be between 0.2 to less than 15 mg, preferably between 0.2 and 12 mg, and more preferably between 0.2 to less than 5 mg.
  • the dosages over a period of 10 days are between 0.2 to less than 10 mg, most preferably between 0.2 and 7.5 mg.
  • the dosages over a period of 10 days are between 1 mg to 30 mg, more preferably between 5 mg and 30 mg.
  • the dose can also be calculated on the basis of the body surface area (BSA) of the subject.
  • the dose of the agent to the subject is from 0.10 to 20 mg/m 2 body surface area of the patient, preferably from 0.12 to 15 mg/m 2 , more preferably 0.20 to 10 mg/m 2 and most preferably 0.30 to 0.50 mg/m 2 .
  • the dose can be calculated based on the body weight of the subject.
  • the dose of the agent to the subject is from 1 to 500 ⁇ g/kg, preferably 2 to 400 ⁇ g/kg, more preferably 2 to 250 ⁇ g/kg and most preferably 2.5 to 20 ⁇ g/kg.
  • the dosages over a period of 10 days are between 0.20 to 10 mg/m 2 , more preferably between 0.20 to 4 mg/m 2 , or between 2 to 250 ⁇ g/kg, more preferably between 2 to 100 ⁇ g/kg.
  • the dosages over a period of 10 days are between 0.30 to 20 mg/m 2 , more preferably between 0.5 to 20 mg/m 2 , or between 2.5 to 500 ⁇ g/kg more preferably between 20 to 500 ⁇ g/kg.
  • the frequency of administration is not especially limited, provided that it does not interfere with the effectiveness of the treatment. It is preferred that the plurality of doses are administered on at least the following bases: daily, every other day, weekly, every 4 weeks, every 6 weeks, every 12 weeks, every 24 weeks, every calendar month, every 6 calendar months or yearly.
  • the doses may be separated by at least one day, or alternatively by at least one week, or by at least one month or by at least 3 months or by at least 6 months or by at least one year (meaning that the doses are taken every day or every week, or every month or every 6 months or every year).
  • the plurality of doses are taken from every 1 to 31 days, or every 1-12 months.
  • the length of treatment is not especially limited, and typically in treatment of autoimmune diseases, the treatment proceeds indefinitely, or until symptoms are reduced to a manageable level for the patient. Generally the dose is administered to the subject for at least 1 month.
  • kits for a use as defined above wherein the kit comprises a plurality of medicament dosages for simultaneous, sequential or separate administration to a subject.
  • Also provided is a method of treatment of an autoimmune disease which method comprises administering a medicament to a subject, wherein the medicament comprises an agent capable of activating CD4+CD25+ regulatory T cells, and wherein the medicament is administered to the subject in an amount as described above.
  • the agent is a humanized anti-CD4 antibody or fragment or derivative thereof derived from the mouse monoclonal anti-CD4 antibody B-F5
  • the pharmaceutical composition and medicaments used according to the present description are for treating an autoimmune disease.
  • the autoimmune disease is selected from psoriasis, rheumatoid arthritis, multiple sclerosis, type-1 diabetes, inflammatory bowel diseases, Crohn's disease, autoimmune thyreoditis, autoimmune myasthenia gravis, systemic lupus erythematosus, ulcerative colitis, atopic dermatitis, myocarditis and transplantation-related diseases such as graft-versus-host or host-versus-graft reactions, or general organ tolerance issues.
  • the autoimmune disease is psoriasis.
  • Psoriasis is a disorder which causes psoriatic lesions or plaques on the sufferer's skin.
  • PASI Psoriasis Area and Severity Index
  • PASI 0.1 E h + I h + D h A h + 0.2 E u + I u + D u A u + 0.3 E t + I t + D t A t + 0.4 E l + I l + D l A t PASI score ranges from 0-72. A score of 0 means no psoriasis, while a score of 72 represents the most severe psoriasis.
  • the pharmaceutical composition of the present description is capable of treating psoriasis by providing at least a 40 %, and preferably at least a 50 %, improvement in the PASI score of the patient.
  • the subject has a PASI score of at least 10 prior to treatment.
  • the pharmaceutical composition is to be administered intravenously, subcutaneously or intramuscularly in the dosages specified herein.
  • the dose is between 0.2 mg to 7.5 mg, more preferably between 0.3 to 5 mg.
  • the dosage over a period of 10 days is preferably between 0.2 to less than 10 mg.
  • the dose is to be administered subcutaneously or intramuscularly it is preferred that the dose is between 0.2 mg to 30 mg, more preferably between 5 mg to 30 mg.
  • the dosage over a period of 10 days is preferably between 0.2 to less than 25 mg.
  • compositions are for treating rheumatoid arthritis.
  • Rheumatoid arthritis is an autoimmune disease which causes chronic inflammation of joints and surrounding tissues, and can also affect other tissues and body organs.
  • ACR American College of Rheumatology
  • CRP C-reactive protein
  • compositions for treating rheumatoid arthritis are preferably to be administered intravenously, subcutaneously or intramuscularly in the dosages specified herein.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Secondary treatment of arthritis includes corticosteroids (e.g. prednisone and dexamethasone), slow acting antirheumatic drugs (SAARDs) or disease-modifying antirheumatic drugs (DMARDs), e.g., methotrexate, penicillinamine, cyclophosphamide, gold salts, azothipoprine, leflunomide, etc.
  • Corticosteroids the synthetic versions of the body's cortisone hormone, are used to inhibit RA progression (e.g. prednisone and dexamethasone).
  • BRMs biological-response modifiers
  • compositions are to be administered in combination with drugs currently used to treat rheumatoid arthritis.
  • the compositions are to be administered with one of the drugs mentioned above, preferably methotrexate.
  • Known drugs such as methotrexate
  • the pharmaceutical composition of the present invention can be administered simultaneously, sequentially or separately.
  • Human PBMCs were isolated by density gradient centrifugation and stained with FITC-labelled anti-CD3 antibody (345763; Becton/Dickinson) and serial dilutions of BT061.
  • BT061 binding was detected with an phycoerythrin labelled human IgG antibody (109-116-098; Jackson, Immunoresearch).
  • flow cytometric analysis the mean fluorescence intensity of CD3+ BT061 binding lymphocytes was determined.
  • BT061 binds to human lymphocytes at low concentrations. Below 10 ng/ml the half maximal saturation of binding is observed. Saturation is found at 100 ng/ml. The concentrations are as expected for patients which receive doses of 30 and 300 ⁇ g.
  • EXAMPLE 2 Inhibition of proliferation of CD8+ T-cells by BT061-stimulated T reg cells (results shown in figure 7)
  • CD25 high Tregs were separated from buffy coats and/or leukapheresis of healthy volunteers by magnetic bead cell separation according to the following protocol.
  • CD4 + CD25 + regulatory T cells were isolated from buffy coats of healthy volunteers by 2 steps.
  • CD4 + T cells using 2-4 ⁇ l CD4-MACS-Multisort-Beads (Miltenyi Biotec) per 10 7 PBMCs were positively selected. After 15 minutes of incubation, magnetic selection was performed.
  • positively isolated cells were depleted of CD25-expressing non-CD4 cells with CD8-, CD19- and CD14-Dynabeads (Dynal, Oslo, Norway). The resulting CD4 + CD25 + T cells were 95-98% pure.
  • Untouched CD4 + CD25 - T cells were isolated by negative selection from PBMC by depleting CD8, CD19, CD56, CD14, CD235a, CD25 and CD45RO expressing cells with Dynabeads.
  • the purification scheme is shown in Figure 2 .
  • BT061 reproducibly induces suppressive activity in Tregs in a dose-dependent manner, resulting in inhibition of the proliferation of alloreactive CD8+ T cells. BT061 stimulates CD4+CD25+ Tregs which directly inhibit CD8+ T cells.
  • results confirm that there is inhibition of the proliferation of CD8+ T cells at concentrations as low as 10ng/ml corresponding to low dose application in patients of 30 ⁇ g.
  • hB-F5 BT061 The ability of hB-F5 BT061 to treat an autoimmune disease is being tested on 56 patients suffering from moderate to severe chronic psoriasis.
  • the trial comprises a single dose escalation study to assess the safety and efficacy of hB-F5.
  • the antibody/placebo is to be infused in the forearm vein according to medically accepted procedures.
  • the total volume is administered as a single continuous intravenous infusion over a period of 2 hours via a perfusor (Fresenius Pilot C, Fresenius AG, Germany).
  • Each dose of the antibody is diluted with a 0.9% sodium chloride injection (B. Braun Melsungen AG, Germany) up to a total volume of 20 ml.
  • the antibody is to be administered as a single subcutaneous injection.
  • the same procedure applies for the placebo.
  • PASI Psoriasis Area and Severity Index
  • the patient's PASI score is assessed before the trial to provide a "baseline" value at day 0, and repeatedly during the trial at days 5, 7, 14, 21, 28, 42, 56 and 75.
  • the PASI scores for the patients in dose group I are shown in Table C together with the percentage improvement in the PASI score from the baseline.
  • the PASI scores for the patients in dose group II are shown in Table D1 together with the percentage improvement in the PASI score from the baseline.
  • the PASI scores for the patients in dose group III are shown in Table D2 together with the percentage improvement in the PASI score from the baseline.
  • PASI scores for the patients in dose group IV are shown in Table D3 together with the percentage improvement in the PASI score from the baseline. TABLE C - PASI scores for the patients in dose group I (0.5mg intravenous dose) over course of trial Patient 1 2 3 4 5 6 7 8 Rel.
  • the PASI scores against time for individual patients are shown in graph form in Figures 8A to 8H and in Figures 9A to 9H .
  • the graphs shown in Figures 8A to 8H represent PASI scores for patients from dose group I, while the graphs shown in Figures 9A to 9H represent PASI scores for patients from dose group II.
  • Patients in dose group III also show an improvement in their PASI score, with six out of eight patients showing a greater than 20% improvement and two of those six showing a greater than 30% improvement after treatment. However, the improvement was not as significant as that seen in patients from dose group I and dose group II which received a lower dose of the antibody. Some efficacy is also seen in the patients of dose group IV. In particular patients 1, 4, 5 and 8 in this dose group (as shown in Table D3) show a clear improvement in their PASI scores, although this is limited in comparison to patients of dose groups I to III.
  • Figures 14A and 14B provide photographic evidence of the improvement in the level of psoriasis before and after treatment.
  • Figure 14A shows an area of psoriasis on the skin of a patient in dose group II prior to administration.
  • Figure 14B shows the same area of psoriasis 28 days after administration. The areas of improvement are marked on Figure 14B with black boxes.
  • BT061 provides effective treatment of moderate and severe chronic psoriasis even with a dose as low as 0.5mg. Further, the single dose provides a therapeutic effect which can still be seen six to eight weeks afterwards.
  • BT061 Thirty volunteers received BT061 by intravenous administration in 10 dosage groups, with 3 volunteers per group. Further, 15 volunteers received BT061 by subcutaneous administration in 5 dosage groups also with 3 volunteers per group.
  • the administration of BT061 intravenously is illustrated Table F below: TABLE F - Intravenous dose of BT061 Administration of BT061 Total dose of BT061 mab Volume of BT061-12.5 mg Volume of BT061-25 mg Volume of BT061-50 mg 3.5 ⁇ g 0.28 ⁇ l - - 20 ⁇ g 1.6 ⁇ l - - 100 ⁇ g 8 ⁇ l - - 500 ⁇ g 40 ⁇ l - - 2.5 mg 0.2 ml - - 5 mg 0.4 ml - - 10 mg 0.8 ml - - 20 mg - 0.8 ml - 40 mg - - 0.8 ml 60 mg 0.8 ml - 1 ml
  • Each dose is diluted with 0.9% sodium chloride injection up to a total volume of 20 ml.
  • the dose is administered as a single continuous intravenous infusion over 2 hours.
  • BT061 subcutaneously is illustrated in Table G below: TABLE G - Subcutaneous dose of BT061 Administration of BT061 Total dose of BT061 mab Volume of BT061-12.5 mg Volume of BT061-25 mg Volume of BT061-50 mg 5 mg 0.4 ml - - 10 mg 0.8 ml - - 20 mg - 0.8 ml - 40 mg - - 0.8 ml 60 mg - - 1 ml + 0.2 ml
  • Each dose is injected as a single bolus injection.
  • the volunteers were assessed over a period of 3 months after the injection.
  • plasma samples were taken before administration and at 3, 6, 12, 24, 36, 48, 56, 72, 88, 96, 120, 144 and 168 hours after administration and on day 75.
  • plasma samples were taken before administration and at 30 minutes, 1, 2, 3, 6, 12, 24, 36, 48, 72, 96, 120, 144 and 168 hours after administration.
  • the plasma samples were analyzed using standard ELISA methodology to establish cytokine levels.
  • the relevant cytokines analyzed included: IFN- ⁇ , TNF- ⁇ , IL-6 and IL-2.
  • the plasma samples were also analyzed using standard methods of flow cytometry to measure the number of CD4+ lymphocytes.
  • Induction of cytokine release is a common immediate complication occurring with the use of T cell interacting therapeutic antibodies, such as ATG, OKT3, CAMPATH-1H and humanized anti-CD3 mAbs (TRX4, Visilizumab and Teplizumab).
  • T cell interacting therapeutic antibodies such as ATG, OKT3, CAMPATH-1H and humanized anti-CD3 mAbs (TRX4, Visilizumab and Teplizumab).
  • TRX4 Visilizumab and Teplizumab
  • the symptoms mainly include moderate fever, headaches and self-limiting gastrointestinal manifestations.
  • Side effects correlated with cytokine induction after antibody administration require the application of additional drugs such as the antihistamine diphenhydramine hydrochloride and/or the anti-inflammatory agent ibuprofen.
  • OKT3 muromonab-CD3
  • a murine CD3 specific therapeutic monoclonal antibody there have even been deaths reported, and severe side effects limit the clinical use of this antibody mainly to immunosuppressed patients.
  • humanized FcR-non-binding CD3-specific monoclonal antibodies that are presently used in the clinic for the treatment of autoimmune disease (Teplizumab and TRX4) exhibit reduced side effects induced by T-cell activation and/or by activation of Fc receptor expressing cells after the first dose, as compared with FcR-binding CD3-specific antibodies such as OKT3, some degree of T-cell activation and activation of Fc receptor expressing cells is still observed that leads to cytokine release generally connected to cytokine dependent side effects.
  • cytokine induction observed in healthy volunteers after intravenous or subcutaneous application of BT061 was comparably low and transient as compared to anti-CD3 antibodies. Cytokine induction generally increased with increasing dosage. However, even at the highest doses of 40 to 60 mg cytokine induction is much lower than that seen with other T cell interacting monoclonal antibodies.
  • the median peak concentration for each cytokine is calculated as follows: The median of the highest cytokine concentrations observed after administration of the antibody.
  • Figure 10A and B show the TNF ⁇ and IL-6 release observed in healthy volunteers after intravenous or subcutaneous administration of BT061 in comparison to those released after administration of anti-CD3 monoclonal antibodies, Teplizumab and TRX4.
  • the normal values of these cytokines were taken from Straub et al., (2007, Arthr. & Rheumat.).
  • Figure 11 shows the IL-2 and IFN- ⁇ plasma levels after administration of intravenous or subcutaneous BT061.
  • the median peak levels were calculated from the 40 and 60 mg dose group measured within 4 days after antibody injection.
  • BT061 induced only marginal and transient cytokine release. TNF- ⁇ and IL-6 levels were slightly increased.
  • Figure 10A and B shows that the median peak values of IL-6 and TNF ⁇ cytokine levels detected in plasma after application of BT061 (40 and 60 mg) are lower than those seen after treatment with the CD3 specific therapeutic antibodies Teplizumab and TRX4.
  • BT061 did not lead to substantially increased levels of IFN- ⁇ and IL-2 ( Figure 11 ) as was reported for the application of TRX4 ( Keymeulen et al., 2005 N. Engl. J. Med. Type 1 Diabetes patients).
  • the trial also included a study of the numbers of CD4-positive lymphocytes in plasma samples collected.
  • Figure 12 shows the CD4 cell counts (cells per ml plasma) in volunteers treated with the single intravenous dose of BT061.
  • the data points represent the mean values of the 3 patients in each dose group.
  • Dotted lines indicate the upper limit of normal (ULN) and the lower limit of normal (LLN).
  • the ULN and the LLN were calculated based on cell counts measured in 11 healthy volunteers using identical methodology to that used to measure the cell counts in those volunteers receiving BT061.
  • the ULN and the LLN represent the mean of all the 11 healthy volunteer values + (or -) the standard deviation.
  • Norm values for CD4 cell counts were calculated to be between 443 CD4 cells per ⁇ l (lower limit of normal; LLN) and 1324 CD4 cells per ⁇ l (upper limit of normal; ULN).
  • Figure 13 shows the CD4 cell counts (cells per ml plasma) in volunteers treated with the single subcutaneous dose of BT061. As with Figure 12 , the data points represent the mean values of the 3 patients in each dose group. Dotted lines indicate the upper limit of normal (ULN) and the lower limit of normal (LLN).
  • CD4 specific monoclonal antibodies known in the art (such as those reviewed in Strand et al., 2007) achieve immuno-suppression via CD4-positive lymphocyte depletion.
  • the drawback of these antibodies is that treated individuals become immuno-compromised, and are susceptible to other infections.
  • CD4 cell counts in four volunteers of the intravenous dose groups showed CD4 levels that were below these norm values as follows: 1 volunteer of the 100 ⁇ g intravenous dose: 400 CD4 cells per ⁇ l; 1 volunteer of the 5 mg group: 419 CD4 cells per ⁇ l; 1 volunteer of the 10 mg group: 440 CD4 cells per ⁇ l; and 1 volunteer of the 20 mg group: 392 CD4 cells per ⁇ l.
  • CD4 cell counts in the remaining 26 volunteers of the intravenous dose groups were within the norm values 72 hours after administration of BT061.
  • BT061 in contrast to depleting CD4 specific mAbs, BT061 only induced a transient decline of CD4-positive cells followed by a general recovery. From the transient decline and rapid general recovery to norm values it is concluded that a transient redistribution of the CD4-positive cells has taken place, rather than depletion of these cells.
  • the ability of hB-F5 BT061 to treat rheumatoid arthritis is being tested on patients suffering from this disease.
  • the trial comprises a multiple dose study involving 96 patients, divided into 12 groups. In each group two patients receive a placebo while 6 patients receive BT061. Patients are dosed once a week over a period of 6 weeks.
  • the subcutaneous dose groups are: 1.25 mg, 6.25 mg. 12. 5 mg, 25 mg, 50 mg, 75 mg and 100 mg.
  • the intravenous dose groups are: 0.5 mg, 2 mg, 6.25 mg, 12.5 mg and 25 mg.
  • the patients are numbered 101, 102, 103, 104, 105, 106, 107 and 108.
  • the patients are numbered 201-208.
  • the patients are numbered 301-308.
  • the patients are numbered 401-408.
  • the patients are numbered 501-508.
  • the 6.25 mg intravenous dose group the patients are numbered 601-608.
  • the intravenous and subcutaneous administration procedure was the same as that described in Example 3 for the psoriasis trial.
  • the level of rheumatoid arthritis is recorded weekly by assessing the ACR parameters and in particular studying the number of tender and swollen joints and following the levels of C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR). These parameters are assessed before the trial to provide a "baseline” value at day 0, and repeatedly during the trial period and thereafter at 8, 22 and 43 days after the administration period is finished (i.e. follow up (FU) day 8, FU day 22 and FU day 43).
  • CRP C-reactive protein
  • ESR erythrocyte sedimentation rate
  • Tables below provide the data obtained from the trial. Specifically Tables M to S provide the number of tender and swollen joints over the course of the trial.
  • Figure 15 shows the percentage of patients from the dose groups receiving 1.25 mg. 6.25 mg, 12.5 mg and 25 mg subcutaneous BT061 achieving at least a 20% improvement of relevant ACR parameters over the course of the trial, and the percentage of patients achieving at least an ACR20 response at week 7.
  • Figure 16A and 16B show results for the number of tender and swollen joints exhibited by patients from the 25 mg subcutaneous BT061 dose group over a six week period. Several patients exhibit a reduction in the number of tender and swollen joints over a period of the treatment. The results for one responder patient and one non-responder patient from this dose group are shown in Figures 17A and 17B , respectively. The responder shows a significant improvement in the number of tender and swollen joints and in pain levels.
  • Figures 18A, 18B , 19A and 19B show the number of tender joints in the 1.25 mg subcutaneous, 6.25 mg subcutaneous, 50 mg subcutaneous and 6.25 mg intravenous dose groups respectively, over the course of the trial and in the weeks thereafter.

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Claims (13)

  1. Composition pharmaceutique pour une utilisation dans le traitement du psoriasis ou de la polyarthrite rhumatoïde, comprenant un support pharmaceutiquement acceptable et un anticorps anti-CD4 humanisé capable d'activer les lymphocytes T régulateurs CD4+CD25+, ladite composition étant destinée à être administrée à un sujet à une dose de l'anticorps anti-CD4 humanisé de 0,2 mg à 5 mg et étant destinée à être administrée par voie intraveineuse, ladite composition étant destinée à être administrée de manière hebdomadaire, toutes les deux semaines, toutes les quatre semaines, tous les mois ou toutes les six semaines,
    dans laquelle l'anticorps anti-CD4 humanisé comprend un domaine V de chaîne H, un domaine V de chaîne L et un domaine constant de IgG1,
    et dans laquelle le domaine V de chaîne H est défini par la SEQ ID N° 1 et le domaine V de chaîne L est défini par la SEQ ID N° 2.
  2. Composition pharmaceutique pour une utilisation suivant la revendication 1, ladite composition étant destinée à être administrée à une dose de l'anticorps anti-CD4 humanisé de 0,3 mg à 1 mg.
  3. Composition pharmaceutique pour une utilisation dans le traitement du psoriasis ou de la polyarthrite rhumatoïde chez un sujet, comprenant un support pharmaceutiquement acceptable et un anticorps anti-CD4 humanisé capable d'activer les lymphocytes T régulateurs CD4+ CD25+, le sujet étant destiné à recevoir une pluralité de doses de la composition, la composition étant destinée à être administrée au sujet à une dose totale de l'anticorps anti-CD4 humanisé pendant une période de temps de 10 jours entre 0,2 et 7,5 mg, la composition étant destinée à être administrée par voie intraveineuse,
    dans laquelle l'anticorps anti-CD4 humanisé comprend un domaine V de chaîne H, un domaine V de chaîne L et un domaine constant de IgG1,
    et dans laquelle le domaine V de chaîne H est défini par la SEQ ID N° 1 et le domaine V de chaîne L est défini par la SEQ ID N° 2.
  4. Composition pharmaceutique pour une utilisation dans le traitement du psoriasis ou de la polyarthrite rhumatoïde, comprenant un support pharmaceutiquement acceptable et un anticorps anti-CD4 humanisé capable d'activer les lymphocytes T régulateurs CD4+CD25+, ladite composition étant destinée à être administrée à un sujet à une dose de l'anticorps anti-CD4 humanisé de 2 à 20 µg/kg et étant destinée à être administrée par voie intraveineuse, ladite composition étant destinée à être administrée de manière hebdomadaire, toutes les deux semaines, toutes les quatre semaines, tous les mois ou toutes les six semaines,
    dans laquelle l'anticorps anti-CD4 humanisé comprend un domaine V de chaîne H, un domaine V de chaîne L et un domaine constant de IgG1,
    et dans laquelle le domaine V de chaîne H est défini par la SEQ ID N° 1 et le domaine V de chaîne L est défini par la SEQ ID N° 2.
  5. Composition pharmaceutique pour une utilisation suivant la revendication 4, ladite composition étant destinée à être administrée à une dose de l'anticorps anti-CD4 humanisé de 20 µg/kg.
  6. Composition pharmaceutique pour une utilisation suivant l'une quelconque des revendications précédentes, ladite composition étant fournie en un volume de dose de 0,5 à 500 ml, de préférence de 15 à 25 ml.
  7. Composition pharmaceutique pour une utilisation suivant l'une quelconque des revendications 1, 2, 4 et 5, la dose étant destinée à être administrée une fois par semaine, une fois toutes les deux semaines ou une fois toutes les quatre semaines.
  8. Composition pharmaceutique pour une utilisation suivant l'une quelconque des revendications 1, 2, 4 et 5, la dose étant destinée à être administrée de manière hebdomadaire ou mensuelle.
  9. Utilisation d'un anticorps anti-CD4 humanisé capable d'activer les lymphocytes T régulateurs CD4+ CD25+ pour la production d'une composition pharmaceutique pour le traitement du psoriasis ou de la polyarthrite rhumatoïde, dans laquelle la composition ést destinée à être administrée à un sujet à une dose de l'anticorps anti-CD4 humanisé de 0,2 mg à 5 mg et est destinée à être administrée par voie intraveineuse, dans laquelle la composition est destinée à être administrée de manière hebdomadaire, toutes les deux semaines, toutes les quatre semaines, tous les mois ou toutes les six semaines,
    dans laquelle l'anticorps anti-CD4 humanisé comprend un domaine V de chaîne H, un domaine V de chaîne L et un domaine constant de IgG1,
    et dans laquelle le domaine V de chaîne H est défini par la SEQ ID N° 1 et le domaine V de chaîne L est défini par la SEQ ID N° 2.
  10. Utilisation d'un anticorps anti-CD4 humanisé capable d'activer les lymphocytes T régulateurs CD4+CD25+ pour la production d'une composition pharmaceutique pour le traitement du psoriasis ou de la polyarthrite rhumatoïde chez un sujet, dans laquelle le sujet est destiné à recevoir une pluralité de doses de la composition, dans laquelle la composition est destinée à être administrée au sujet à une dose totale de l'anticorps anti-CD4 humanisé pendant une période de temps de 10 jours entre 0,2 mg et 7,5 mg, dans laquelle la composition est destinée à être administrée par voie intraveineuse,
    dans laquelle l'anticorps anti-CD4 humanisé comprend un domaine V de chaîne H, un domaine V de chaîne L et un domaine constant de IgG1,
    et dans laquelle le domaine V de chaîne H est défini par la SEQ ID N° 1 et le domaine V de chaîne L est défini par la SEQ ID N° 2.
  11. Utilisation d'un anticorps anti-CD4 humanisé capable d'activer les lymphocytes T régulateurs CD4+CD25+ pour la production d'une composition pharmaceutique pour le traitement du psoriasis ou de la polyarthrite rhumatoïde, dans laquelle la composition est destinée à être administrée à un sujet à une dose de l'anticorps anti-CD4 humanisé de 2 à 20 µg/kg, dans laquelle la composition est destinée à être administrée par voie intraveineuse, dans laquelle la composition est destinée à être administrée de manière hebdomadaire, toutes les deux semaines, toutes les quatre semaines, tous les mois ou toutes les six semaines,
    dans laquelle l'anticorps anti-CD4 humanisé comprend un domaine V de chaîne H, un domaine V de chaîne L et un domaine constant de IgG1,
    et dans laquelle le domaine V de chaîne H est défini par la SEQ ID N° 1 et le domaine V de chaîne L est défini par la SEQ ID N° 2.
  12. Utilisation suivant la revendication 9 ou la revendication 11, dans laquelle la dose est destinée à être administrée : (i) une fois par semaine, une fois toutes les deux semaines ou une fois toutes les quatre semaines ; ou (ii) de manière hebdomadaire ou mensuelle.
  13. Utilisation suivant l'une quelconque des revendications 9 à 12, dans laquelle la composition est fournie en un volume de dose de 0,5 à 500 ml, de préférence de 15 à 25 ml.
EP09727585.3A 2008-03-13 2009-03-10 Schema posologique pour traiter le psoriasis et l'arhtrite rhumatoide Not-in-force EP2265643B1 (fr)

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GB0804686A GB0804686D0 (en) 2008-03-13 2008-03-13 Humanized antibody
GB0817811A GB0817811D0 (en) 2008-09-29 2008-09-29 Agent for treating disease
PCT/EP2009/052809 WO2009121690A1 (fr) 2008-03-13 2009-03-10 Agent pour traiter une maladie

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CA (1) CA2718184A1 (fr)
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KR20100135257A (ko) 2010-12-24
BRPI0909048A2 (pt) 2015-11-24
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CR11724A (es) 2011-06-07
ZA201007215B (en) 2016-08-31
AU2009231325B2 (en) 2014-09-18
JP5597553B2 (ja) 2014-10-01
IL207891A0 (en) 2010-12-30
EP2265643A1 (fr) 2010-12-29
US9334325B2 (en) 2016-05-10
JP2011516416A (ja) 2011-05-26
MX2010010028A (es) 2011-08-17
CO6311007A2 (es) 2011-08-22
RU2010141826A (ru) 2012-04-20
SG190598A1 (en) 2013-06-28
CN102027017A (zh) 2011-04-20
RU2539110C2 (ru) 2015-01-10
WO2009121690A1 (fr) 2009-10-08
AU2009231325A1 (en) 2009-10-08

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